Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr Mohan Z Mani

"Thank you very much for having published my article in record time.I would like to compliment you and your entire staff for your promptness, courtesy, and willingness to be customer friendly, which is quite unusual.I was given your reference by a colleague in pathology,and was able to directly phone your editorial office for clarifications.I would particularly like to thank the publication managers and the Assistant Editor who were following up my article. I would also like to thank you for adjusting the money I paid initially into payment for my modified article,and refunding the balance.
I wish all success to your journal and look forward to sending you any suitable similar article in future"



Dr Mohan Z Mani,
Professor & Head,
Department of Dermatolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



Dr Kalyani R
Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
‘Knowledge is treasure of a wise man.’ The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011
Anuradha

Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.


Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020

Important Notice

Reviews
Year : 2012 | Month : May | Volume : 6 | Issue : 3 | Page : 510 - 516

The Changing Facade of Anti-arrhythmics

Thomas Joseph, Princy Louis Palatty

1. Intern, Father Muller Medical College Mangalore, Karnataka, India. 2. Professor, Department of Pharmacology Father Muller Medical College Mangalore, Karnataka, India.

Correspondence Address :
Princy Louis Palatty
Professor, Department of Pharmacology
Mangalore -2, Karnataka, India
Phone: 0824-38000
E-mail: drprincylouispalatty@gmail.com

Introduction
There has been an overwhelming rise in the number of cardiovascular diseases over the past few decades. In the nineties, it was found that there were around 50 million deaths world wide, of which 14 million were contributed by heart diseases alone. Since then, the number of cardiovascular diseases have not dwindled. Ischaemic heart disease is estimated to become the top ranked cause of worldwide deaths by the year 2020. The mortality and the morbidity which is caused by this disease is due to its complications. Arrhythmias have been attributed to be a major cause of death following myocardial infarction and stroke. Over the years, cardiac arrhythmias have been one of the major health problems which were extensively studied upon, in terms of their mechanism and treatment. Ironically, they are one of the medical problems which has been very difficult to fathom. Many drugs have been approved for their treatment, but yet a large group of people who were suffering from them never responded as expected or they had side effects of the drug. The symptomatic limitations and the mortality which are connected to this condition has led researchers to push themselves to find new drugs with a robust treatment mechanism and lesser side effects. The growing financial burden which was indirectly caused by their morbidity and mortality could be eased by defining a new anti-arrhythmic with lesser side effects.

Atrial fibrillation is the most common type of arrhythmia. Inspite of ablation being effective in atrial fibrillation, it is pharmacotherapy that holds the mainstay. Researchers are working hard to unravel drugs which are more selective in their actions. The reputation of anti-arrhythmics as pro-arrhythmics should be contained. To reduce their side effects, the pursuit of multi-channel blockers would be promising. All in all, pharmacotherapy has been the mainstay in the treatment of cardiac arrhythmias. The fact that these drugs themselves caused life threatening arrhythmias and extra cardiac side effects, has led to the generation of an interest among scientists to come up with novel drugs (Table/Fig 1).

The mechanism of Arrhythmogenesis (Table/Fig 2)
Arrhythmias occur either due to disorders of the impulse initiation or conduction of the cardiac impulses, which are characterized below:
I) Disorder Of Impulse Initiation (Table/Fig 3)
a) Abnormal Automaticity:
The spontaneous cardiac rhythmicity involves slow depolarization of the trans-membrane voltage during diastole till the threshold potential is attained and an action potential is triggered. This faster paced action potential will take over as the
Reviewpace maker. This phenomenon may be accelerated by changing the threshold potential or by increasing the rate of the diastolic depolarization. Such a change can be affected in any part of the cardiac tissue. Abnormal automaticity is believed to be the cause of sinus tachycardia, escape rhythms and accelerated junctional rhythms.

II) Disorders of Impulse Conduction
a) Triggered activity:
This is due to oscillations of the trans- membrane potential at the end of the action potential which is called depolarization. These may reach a threshold potential and cause arrhythmias. It is known as early depolarization if the trans-membrane potential reaches its threshold. When the after depolarization develops after the trans-membrane potential has been reached, then it is called as delayed after depolarization. Such after depolarizations may occur in cardiac tissues, which may follow myocardial ischaemia or myocardial infarction.

b) Re-entry or circus movement:
This occurs when a ring of cardiac tissue surrounds an inexcitable core. Most of the paroxysmal tachycardias are produced by this mechanism. An arrhythmia is initiated if an ectopic beat finds one limb refractory and the other excitable but slow enough, that a re-entry circuit may be formed when the earlier refractory limb becomes excitable.

ARRHYTHMIAS Cardiac arrhythmia is a phenomenon where there is an abnormality in the cardiac rhythm. Arrhythmia may be broadly classified into bradyarrhythmias and tachyarrhythmias.

I) Bradyarrhythmias
These may be further classified into
a) Sinus Bradycardia: Sinus bradycardia can be caused due to extrinsic or intrinsic factors. External factors affect the normal sinus node functionally, which are commonly drug induced – beta blockers, digitalis, syndromes such as the neurocardiogenic syndrome, the carotid sinus syndrome, etc. Intrinsic factors – these are associated with a sinus node that has a degenerative or a non degenerative disease eg: the Sick Sinus Syndrome, ishcaemic heart disease, cardiomyopathy, myocarditis, etc. Sinus bradycardia is characterized by a decreased heart rate, sinus arrest and syncope.
b) Heart Block: Any hindrance in the conduction of an impulse anywhere in the conductive system is referred to as a heart block.

i) Atrioventricular Block: In this type of block, there is a failure in the conduction of an impulse to the level of the Bundle of His.
ii) Bundle branch block: There is a block in the conduction of an impulse below the level of the Bundle of His.
II) Tachyarrhythmias a) Supraventricular Tachycardias: These arise from the atrioventricular junction or the atrium.
b) Atrial tachyarrhythmias: They include atrial fibrillation, atrial flutter, atria ectopic beats and atrial tachycardia.
c) Ventricular Tachyarrhythmias: These include sustained ventricular tachycardia, ventricular fibrillation, non-sustained ventricular tachycardia and ventricular premature beats.

ANTI-ARRHYTHMIC DRUGS The therapy of arrhythmia is based on the acuteness in its onset, the type of arrhythmia, and the effective interventions (Table/Fig 4). Drugs are the mainstay in the prophylaxis and the treatment of arrhythmias (Table/Fig 5)

Class 1. Sodium Channel Blockers The drugs of this class mainly affect the phase 0 of the action potential. These drugs bind to the alpha units of the sodium channels and inhibit the propagation of the action potential in a majority of the excitable cells. The sodium channel blocking drugs are further divided into 1A, 1B and 1C according to the electro-physiologic difference in the type of block that these drugs exhibit.

CLASS 1A: It is the oldest group among the anti-arrhythmic drugs. They depress the phase 0 of the cardiac action potential (Table/Fig 6). In addition to sodium channel blocking, these drugs also block the potassium channels, thus causing the prolongation of the repolarisation phase of the action potential.

Quinidine: Quinidine is a D isomer which is extracted from the Cinchona bark. Quinidine depresses the propagation of the action potential and it causes depression of all the cardiac properties. The treatment with quinidines should be well monitored as they themselves are highly pro-arrhythmic. They can cause torsade de pointes, sudden cardiac arrest, ventricular fibrillation and angio-oedema. Their alpha 2 blocking properties cause hypotension and vascular collapse.

Procainamide: it has cardio electrophysiological properties which are similar to those of quinidine and it differs from it in terms of being less potent than quinidine.

Procainamide causes CNS effects such as hallucination and mental confusion. It can cause cardiac adverse effects which are similar to those which are caused by quinidine, such as fever, rash and angio-oedema. Diisopyramide: this drug has anti-cholinergic and cardiac depressant activities and unlike quinidine, it has no alpha adrenergic blocking property. The anti-cholinergic side effects are dry mouth, constipation and blurring of vision. It is contraindicated in patients with the sick sinus syndrome. It causes hypotension and cardiac depression in patients with a decompensated heart.

Morcizine: It belongs to a group of phenothiazine derivatives. The Na+ channel recovery is delayed in its case as compared to the other drugs. The CNS effects are less marked with the use of this drug, but the CAST 2 studies have found the drug to have increased the mortality in post MI patients (1).

CLASS 1B: These drugs bind to the open sodium channels during phase 0 of the action potential (Table /Fig 6). They block many of the channels by the time the action potential would have reached its peak. They block the refractory channels, preferentially the cardiac cells which are depolarized.

Lignocaine: The selective action of this drug is seen on partially depolarized cells and damaged ventricular fibres as opposed to the normal ventricular fibres. It reduces after depolarization and automaticity in ectopic foci. Lignocaine is a popular anti-arrhythmic in intensive care units . It is used in post surgical or post-myocardial arrhythmia. Lignocaine is not effective in atrial arrhythmias as the atrial action potentials are short and as there is a lack of the lignocaine effect on the channel recovery. Lidocaine has a very low tendency to be a pro-arrhythmic. It is used in emergency situations because of its rapid and titratable action. It is useful in digitalis induced arrhythmias.

The side effects include paresthaesias, blurring of vision, disorientation, nystagmus and seizures.
Mixeletine: It is an anti-arrhythmic which is pharmacologically similar to lidocaine. It is used in post-infarction ventricular arrhythmias, extra systoles and tachycardia. Its parenteral administration can cause hypotension and bradycardia. It can also cause blurring of vision, dizziness, ataxia, tremor and gastrointestinal discomfort.
Phenytoin: It is an anti-epileptic which has anti-arrhythmic properties. It can be used in ventricular arrhythmias, but it is not usually used due to its side effects.
Aprinidine: it is useful in controlling refractory ventricular tachy-arrhythmias . It is electrophysiologically similar to quinidine.

CLASS 1C: They include the most potent sodium channel blockers. They are usually used in resistant cases. They have their effects on the sodium channels along with a long recovery period (Table /Fig 6). Propafenone is used as a reserve drug for ventricular arrhythmia and reentrant tachycardias. Other class 1C drugs include encainide and flecainide which have an action which is similar to that of propafenone. These drugs can increase the mortality in patients with underlying myocardial infarction. Pilscainide: Pilscainide has selectiveness for the sodium channels, especially in its inactivated state. It was found to be useful in recent onset atrial fibrillation as compared to the earlier drugs of this classwhich were used. Pilscainide has preference for the fast sodium channels which affect phase 0 of the cardiac potential. It decreases the rate of depolarization and the amplitude of the action potential without affecting the timing of the action potential. In randomized multicentric trials, it was found that pilscainide achieved more numbers in the restoration of the sinus rhythm in patients with atrial fibrillation than in those who received the placebo. A single dose of oral pilscainide is capable of the restoration of the normal rhythm in recent onset atrial fibrillation (2).

It showed no superiority in terms of the long term treatment of atrial fibrillation and it exhibited adverse effects which were similar to those which were produced by other class 1 agents .

CLASS 2: BETA BETA BLOCKERS An increased sympathetic activity is said to be the cause for ventricular dysarrhythmias following myocardial infarction. Thus, adrenoreceptor antagonists play major roles as an anti-arrhythmics.
Propranolol: In addition to its beta blocking property, it has a class 1 activity which contributes to it being an antidysrhythmic drug. It is useful in treating arrhythmias which are induced by emotion, exercise, pheochromocytoma and anaesthetics. It can be used in post myocardial infarction patients as a prophylactic measure against arrhythmias. Bronchospasm is its major side effect, followed by a negative ionotropic effect. Metaprolol and Atenolol are beta 1 selective drugs which help in avoiding the risk of bronchospasms, but their selectivity is not as much as was anticipated in the clinical practice. Still these drugs are in common usage due to their once a day regimen.

Esmolol: This is a fast and short acting beta 1 blocker drug which is useful for arrhythmias following the use of anaesthetics and against supraventricular tachycardia.
CLASS 3: POTASSIUM CHANNEL BLOCKERS
They have the unique action of prolonging the action potential. This process is not really understood, but they block the potassium channels which are involved in the phase of repolarization (Table /Fig 6). They have a tendency to be pro arrhythmic and they also lead to torsade de pointes. Amiodarone: It is a long acting anti-arrhythmic which is highly lipophilic and it is structurally related to thyroxine. It acts by blocking the k+ channels. It preferentially blocks the inactivated Na+ channels and it also inhibits the myocardial action of the calcium channels. Amiodarone is useful in ventricular and supra ventricular arrhythmias. It is also useful in resistant and recurrent arrhythmias. Amiodarone as an intravenous injection helps in the termination of ventricular and supraventricular arrhythmias rapidly. It is useful in patients with sustained ventricular tachycardia.

Amiodarone can cause gastro-intestinal discomfort, photosensitisation, pulmonary alveolitis and peripheral neuropathy as it contains iodine and can cause disorders of the thyroid function.

Sotalol: It is a non-selective beta blocker with a class 3 anti-arrhythmic activity. Sotalol is effective in polymorphic ventricular tachycardia and for maintaining the sinus rhythm in atrial fibrillation. Sotalol can cause dose dependant torsade de pointes.
Dofetilide: It selectively blocks the rapid component of the delayed rectifier k+ current. Its primary indication is to maintain a sinusrhythm . Even though this drug has shown a tendency of producing torsades des pointes, it has shown less mortality in patients with the risk of sudden cardiac death and myocardial infarction.

Ibutilide: is a drug which is similar to dofetilide which is used for the conversion of atrial fibrillation to a sinus rhythm. Dronederone: Dronedarone is a benzofuran derivative which is closely related to amiodarone. In this drug, the iodine entity is replaced by a methane sulfonyl group, thus eliminating the probable neurotoxic effects. In experimental studies which were conducted on human atrial myocytes by the whole cell patch clamp technique, dronaderone was observed to inhibit the trans-membrane potassium currents like the ultra rapid- delayed rectifier (Ikur), the delayed rectifier(Iks and Ikr), the transient outward (Ito) and the inward rectifier (Ik1) (3). Studies have shown dronaderone to be effective in the treatment of atrial fibrillation and in controlling the ventricular rates (4).

In January 2011, the FDA had cautioned about cases of rare but severe liver injury with the usage of dronaderone (5).The drug should be immediately stopped if a hepatic injury is suspected. Dronaderone is contraindicated in patients with NYHA class 4 heart failure or NYHA class 2-3 heart failure with a recent decompensation which requires hospitalization. Dronadarone was approved with a Risk Evaluation and Mitigation Strategy (REMS), with the goal of preventing its use in severe heart failure (5).

Vernakalant: Vernakalant is an atrial selective anti-arrhythmic drug and an amino hexyl ether which is used in atrial fibrillation. It selectively blocks the ultra rapid delayed rectifier current (I Kur). Vernakalant causes effective prolongation of the effective refractory period of the atria, with no effect on the ventricles and so, it is less pro-arrhythmic. Vernakalant was found to show better effectiveness than placebo and amiodarone in the rapid conversion of atrial fibrillation (6). Through the ACT studies, transient adverse effects such as dysguaesia, parasthaesia, nausea and hypotension were demonstrated by this drug (7).
Nifekalant: Its action is similar to the action of Vernakalant. Nifekelant has been observed to be effective in atrial fibrillation which was caused by a prolonged atrial effective refractory period. Nifekalant has been shown to be effective in supraventricular tachycardias. The survival was higher in patients with ischaemic heart disease and ventricular tachycardia, who were resistant to the first shock of Nifekalant (8). Unfortunately, Nifekalant causes QT prolongation and torsades des pointes (9).

Niferidil: Niferidil causes blockage of the postassium channels which are involved in the phase of repolarization. It markedly influences the atrial refractoriness and not the ventricular refractoriness. Sinus bradycardia was seen with the usage of Niferidil in some patients.

CLASS 4: CALC IUM CHANNEL BLOCKERS
These drugs act by blocking the L-type calcium channels.
Verapamil: This drug has the most prominent action among the class 4 drugs. It blocks the L type calcium channels and delays their recovery. It is the drug of choice in paroxysmal supraventricular tachycardia. It can be administered by the intravenous route or orally. Verapamil is not used in reentrant supraventricular tachycardia andin the Wolff Parkinson white syndrome due to the risk of ventricular tachycardia which is caused by a reflex sympathetic stimulation.
Diltiazem: Its actions are similar to those of Verapamil, but it is less effective. It is preferred over Verapamil in atrial fibrillation to control the ventricular rate, as it can be easily titrated to the required heart rate.

MISCELLANEOUS DRUGS Adenosine: This is a naturally occurring purine nucleoside which is released during myocardial ischaemia. It activates the Ach sensitive K+ channels and causes membrane hyperpolarization through its interaction with the A1 type of G protein coupled adenosine receptors on the SA node, the AV node, and the atrium. It decreases the Ca2+ current in the AV node indirectly. All these actions lead to the slowing of the action potentials, bradycardia, reduced excitability and slowing of the conduction. Adenosine is at present preferred by many cardiologists for the termination of paroxysmal supraventricular tachycardia.
Adenosine can cause dyspnoea, headache, flushing and bradycardia.

Digoxin: Reduces the ventricular rate. It is indicated in atrial fibrillation with a rapid ventricular rate or in atrial fibrillation with cardiac failure. Digoxin decreases the conduction through the A-V bundle and the A-V node. The rate cannot be brought down in the presence of fever, sepsis and hyperthyroidism and attempts to do so, can lead to toxicity. Digoxin causes multi-focal extra-systoles, sinoatrial arrest, ventricular fibrillation, gastro-intestinal and neurological toxicity.

NEWER ANT IARRHYTHMICS Gap Junction Modifiers:
Gap junctions connect the cytoplasmic compartments of two adjacent cells and bring about an intercellular communication. The electrical syncytial properties and the propagation of the action potential is dependant on the gap junctions (10). Mutations in the genes which encode for the connexins which are components of the gap junctions, may predispose the patient to the development of arrhythmias. Rotagaptide: Rotagaptide is a gap junction modifier , which is also known as a connexin modifier. Studies in dog models have shown the significant use of rotagaptide in reverting atrial fibrillation. Rotagaptide treatment has shown activation of the protein kinase C isoforms, which in turn, could cause the phosphorylation of Cx43, which in turn could cause the proper functioning of the connexins (11). The smoother conductions which are caused by this, leads to a more synchronous contraction of the cardiac musculature.

Adenosine A1 Receptor Agonists:
Adenosine A1 Receptor agonists are highly selective, new anti-arrhythmics which eliminate the non selective effects of adenosine.
Tecadenoson: It is an adenosine derivative with a high specificity to the A1 receptors. It has a tendency to prolong the atrioventricular node conduction. This action is possible without triggering a reduction in the blood pressure or bronchospasm through the stimulation of the A2 receptors. It may prove to be a potent drug for the urgent rate control and the possible cardioversion of atrial fibrillation. It has been found that Tecadenoson is effective in the rapid conversion of paroxysmal supraventricular tachycardia to a sinus rhythm (12).

Paraesthaesia was experienced by some patients with the usage of Tecadenason. Its other side effects included tachycardia, headache and flushing (13).


Selodenoson: This drug is similar to Tecadenoson. Its half life duration is longer than that of Tecadenosone and it is more suitable for oral usage. The intravenous and oral sustained usage of this drug form is under study for chronic management on an outpatient basis (14).
Ranolazine: This is an anti-anginal agent which has the property of blocking the late and peak INa , Na+ /K+ , IKr ,IKs currents. Ischaemia and oxidative injury may be caused by the increased atrial rates, which in turn cause augmentation of the INa currents by causing an intra-cellular increase in the Na+ ions and activation of the Na+/Ca2+ exchangers, causing it to work in reverse mode, bringing calcium into the cell (15). This augmentation of INa+ leads to the promotion of the reentrant arrhythmias. Ranolazine is a potent inhibitor of the late INa current. It has been found to prevent early depolarizations by preventing the calcium and sodium overload in animal models.

Atrial Stretch Receptor Antagonists:(16) Studies have shown that atrial stretch which is caused by dilatation may lead to activation of the stretch receptor channels ,which in turn would lead to electro-physiological effects such as the slowing down and the shortening of the refractory period (17). Gadolinium is a drug which is a non specific stretch receptor antagonist which was found to prevent atrial fibrillation in isolated rabbit hearts. Unfortunately, Gadolinium could not be used in physiological conditions (18).
GSMTX-4: This is an agent in the experimental phase, which is a 35 amino acid peptide toxin which is isolated from the venom of the Chilean Rose tarantula. It selectively blocks the cationic stretch activated channels. It was found to prevent the induction of atrial fibrillation without any effect on the duration and the shape of the atrial action potential. Even though this agent is selective in blocking the stretch activated channels, it are not atrial specific (19). Altering the membrane fluidity- PUFA- The activation of the stretch activated channels depend upon the membrane fluidity. The membrane fluidity can be altered by PUFA. It was found that in rabbits which were PUFA fed, their hearts demonstrated an increased resistance to the stretch mediated changes in the electrophysiological activities. Further studies are required to prove its potential (20).

Renin Angiotensin System Inhibitors: Following the atrial stretch, it has been found that there is a release of angiotensin 2, which in turn would lead to the activation of mitogen activated protein kinases. The mitogen activated protein kinases lead to fibroblast proliferation and I nterstitial fibrosis, which can cause conduction defects. Angiotensin 2 leads to an increased calcium influx and inflammation and it also causes gap junction remodelling, leading to arrhythmias. The superlative effectiveness of the ACE inhibitors in cardiac failure could be because of their proposed anti-arrhythmic effects via angiotensin 2 mediated arrhythmias.

POTENT IAL ANT I-ARRHYTM ICS FOR THE FUTURE GAP134: GAP 134 is a dipeptide gap junction modifier (21). GAP 134 prevents the decrease in the velocity of the conduction of an impulse. It was found that pericarditis models were protected from atrial fibrillation by GAP 134 (21). The limitations of this drug are the doubts about its action on chronically remodeled atria and its proarrhythmic property.

PIRFENIDONE Pirfenidone is an antifibrotic agent. It acts by downregulating the profibrotic cytokines (22), thus inhibiting collagen synthesis. Pirefenidone has been found to have an anti arrhythmic potential through studies on canine models. Pirefenidone, on oral administration, was found to decrease the atrial fibrosis, which led to beneficial electro-physiological effects such as prolongation of the effective atrial refractory period and a decrease in the atrial fibrillation vulnerability (22). ATI 2042 (budiodarone): ATI 2042 is a chemical analogue of amiodarone. It has a half life of 7 hours and it is thought to have an efficacy which is in par with amiodarone. It contains iodine, which is hypothesized to be the cause of the similarity in its efficacy with amiodarone. Unlike amiodarone, its side effect profile is better with regards to long term treatment and tissue accumulation. ATI2042 reduces the time in which the patient was in AF (23). This drug is under the study and it has been focused upon as a future drug in AF.

Chloride Channel Blockers: (24) ion channels such as the L-type Ca2+ channels, the delayed rectifier K+ channels and the Na+ channels are regulated by cAMP dependant protein kinase.These chloride channels which are activated by protein kinase A, have been identified in guinea pigs and the heart chloride channel shows a lot of similarity with the cystic fibrosis trans-membrane conductance regulator chloride channels. Diphenylamine -2carboxylate, anthracene 9 carboxylate, 44’dinitrostilbene-22’-disulfonicacid, indanyloxyaceticacid, p-chlorophenoxypropionic acid and gemfibrozil have been shown to prolong the action potential of the heart by its action on the CFTR chloride channels, thus showing an anti-arrhythmic effect.

GENETHERAPY New strategies are being looked upon for modulating the atrioventricular conduction by the introduction of genetic calcium channel blockers. Adenoviral vectors are being used to carry the inhibitory Gαi2 protein or by the targeted transfer of the Ras-related small G protein, which in turn, regulates the activity of theICaLα subunit to sarcolemma (25). Gene therapy is still under study for future use.

Conclusion

Despite having four classes of anti-arrhythmic agents, the arrhythmias are unhindered, as yet. Newer class 3 agents like Dronaderone and Vernakalant seem to hold a lot of promise without the antecedent adverse effects. Gap junction modifiers, adenosine receptor agonists and ranolazine act on new targets that could have a tolerable safety profile and an enhanced efficacy .

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DOI and Others

DOI: JCDR/2012/3989:2074

Financial OR OTHER COMPETING INTERESTS:
None.


Date of Submission: Jan 14, 2012
Date of Peer Review: Feb 22, 2012
Date of Acceptance: Mar 10, 2012
Date of Publishing: May 01, 2012

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